Discovery of 3-(Fluoro-imidazolyl)pyridazine Derivatives as Potent STING Agonists with Antitumor Activity
Stimulator of interferon genes (STING) represents a promising therapeutic target for cancer and infectious diseases due to its ability to activate innate immune responses. Herein, we describe the discovery of 3-(fluoro-imidazolyl) pyridazine derivatives as potent STING agonists. Our comprehensive investigation, including structural and functional analysis as well as molecular dynamics simulation, suggests that appropriate spatial dimensions may play a crucial role in determining agonist efficacy. Notably, our representative STING agonist <b>A4</b> demonstrates remarkable binding affinities to various hSTING variants and mSTING, effectively activating STING in both human THP1 and mouse RAW 264.7 cells with EC<sub>50</sub> values of 0.06 and 14.15 μM, respectively. Furthermore, Compound <b>A4</b> exhibits an excellent pharmacokinetic profile in C57BL/6 mice, and its systemic administration led to significant tumor regression in the B16.F10 tumor-bearing mice, surpassing the efficacy of <b>SR-717</b>. These findings position <b>A4</b> as a highly promising STING agonist warranting further advanced preclinical development for tumor immunotherapy.
Authors
- Ning Ma (ORCID: https://orcid.org/0000-0002-6473-595X)
- Rongrong Cui
- Bing Jiang (ORCID: https://orcid.org/0000-0001-5389-3293)
- Keke Zhang (ORCID: https://orcid.org/0000-0002-5755-7059)
- Jingyi Zhou (ORCID: https://orcid.org/0000-0002-7020-598X)
- Changfa Zhang (ORCID: https://orcid.org/0000-0002-7238-5152)
- Qibang Sui (ORCID: https://orcid.org/0009-0008-0097-520X)
- Manjia Li
- Peijia Xu
- Mingyue Zheng (ORCID: https://orcid.org/0000-0002-3323-3092)
- Hui Hou (ORCID: https://orcid.org/0000-0001-8974-197X)
- Zhaoming Su (ORCID: https://orcid.org/0000-0002-9279-1721)
- Bin Shan (ORCID: https://orcid.org/0000-0001-7800-0762)
- Yajie Wang (ORCID: https://orcid.org/0000-0002-7023-4844)
- Zhengyang Chen
- Sulin Zhang (ORCID: https://orcid.org/0000-0002-9167-4689)
- Dan Teng
Institutions
- Nanjing University of Chinese Medicine (CN)
- Chinese Academy of Sciences (CN)
- ShanghaiTech University (CN)
- Shanghai Institute of Materia Medica (CN)
- Drug Discovery Laboratory (Norway) (NO)
- Institute for Advanced Study (DE)
- University of Chinese Academy of Sciences (CN)
- State Key Laboratory of Drug Research
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-05-09
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01873
- Citations
- 3
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 2.39
Funders
- Natural Science Foundation of Shanghai
- China Association for Science and Technology
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- China Postdoctoral Science Foundation
- Youth Innovation Promotion Association of the Chinese Academy of Sciences
- Shanghai University of Traditional Chinese Medicine
- State Key Laboratory of Pharmaceutical Biotechnology
- National Key Research and Development Program of China
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences